Allergic diseases such as atopic dermatitis, asthma, allergic rhinitis and allergic conjunctivitis are diseases in which hypersensitive reactions occur against environmental antigens to which normal healthy people do not react and destruction and disorders of various organs occur due to the autoimmune system. As an onset mechanism of these diseases, there has been considered the enhanced allergic reactions caused by Th2 type cytokines such as interleukin-4 and interleukin-5 that the Th2 cells among the Th differentiate involved in cellular immune responses against antigen (Progress in Medicine 17: 19-20, 1997). The elucidation of the induction mechanism and the control mechanism has important physiological and pharmacological implications, but detailed mechanisms thereof have yet to be clarified. Therapies of these diseases in current use include evasion from antigen, the control of non-specific inflammatory reactions by the oral administration of antihistamines that antagonize the binding of mediators such as histamine to receptors and by topical steroid (Igaku No Ayumi (Journal of Clinical and Experimental Medicine) 180: 51-55, 1997).
For the treatment of allergic diseases, there can be conceived the suppression of allergic reactions by shifting the Th2 type cytokine-dominant allergic state to the Th1 type cytokine-dominant state, and since interferon-γ produced by Th1cells suppresses the effect of enhancing IgE production by interleukin-4 produced by Th2 cells (Progress in Medicine 17: 19-20, 1997), interferon-γ has been in trial use for the treatment of allergic diseases (J. Am. Acad. Dermatol. 32: 684-685, 1991; Allergy 49: 120-128, 1994; Acta Derm. Venereol 73: 130-132, 1993), but the effect is small and the results have not been satisfactory, and thus has not been subjected to clinical uses.
For the establishment of atopic diseases, the maintenance of the Th2 type-dominant immunological state and the maintenance of ensuing inflammatory reactions are involved. For the improvement of the Th2 type-cytokine dominant immunological state, control of cytokines by immunosuppressive agents has been attempted (Br. J. Dermatol. 143: 365-72, 2000; J. Allergy Clin. Immunol. 106 (1 pt2): S58-64, 2000), but that did not lead to the essential improvement of the immunological state and thereby had a limited effect.
On the other hand, BCG vaccine is a vaccine that utilizes an attenuated strain of Mycobacterium bovis and is the only live vaccine approved for Mycobacterium tuberculosis infections. BCG vaccine has a potent adjuvant effect with little side effects, and thus has been given to many people in the world today as a safe vaccine. Now, BCG vaccine has been reported to have an activity of shifting CD4+ helper T cells to Th1 cells that are responsible for cell-mediated immunity by producing interferon-γ and interleukin-2 (Cancer Immunol. Immunother. 39: 401-406, 1994; ibid. 40: 103-108, 1995).
As a protein that is omnipresent among Mycobacteria, the antigen 85 complex was identified. The protein complex is composed of an antigen 85 complex-forming protein 85A with a molecular weight of about 30-32 kd (Infect. Immun. 57:3123-3130, 1989), an antigen 85 complex-forming protein 85B (J. Bacteriol. 170: 3847-3854, 1988) and an antigen 85 complex-forming protein 85C (Infect. Immun. 59: 3205-3212, 1991), which are major secretory proteins of Mycobacteria. These secretory proteins exhibit high homology of the gene sequence and the amino acid sequence and cross reactivity to monoclonal antibodies among the bacteria of the same genera such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium kansasii etc. irrespective of the species (Microbiol. Rev. 56: 648-661, 1992) and have, as common functions, the activity of binding to fibronectin and of mycolyl group transferase in the cell wall synthesis (Microbiol. Rev. 56: 648-661, 1992; Science 276: 1420-1422, 1997; Nat. Struct. Biol. 7: 887-88, 2000). Among these secretory proteins, the antigen 85 complex-forming protein 85B is widely known as α antigen.
Currently, furthermore, α antigen has been isolated and purified as a tuberculin reactive protein from the culture supernatant of Mycobacterium tuberculosis, and it has been revealed, there is an epitope in the molecule (Am. Rev. Respir. Dis. 130: 647-649, 1984; ibid. 132: 173-174, 1985; Microbiological Reviews 56: 648-661, 1992), and it has been reported that this α antigen has the above-mentioned effect of shifting to the Th1 cells (Infect. Immun. 60: 2880-2886, 1992). Attempts have also been made to use and improve Bacillus Calmette-Guerin by recombinant DNA technology, and then to use as a vaccine to various pathogens. For example, it has been reported, an expression vector was constructed in which a gene encoding the surface antigen of AIDS virus was integrated into the gene containing the α antigen, and the vector was used to transform Bacillus Calmette-Guerin, which transformant is used as a BCG vaccine (WO 96/4009).
Up until today, however, no attempts have been made to use a gene encoding the α antigen or the α antigen per se for the treatment of allergic diseases. Furthermore, though the α antigen has been reported to have the effect of shifting CD4+ helper T cells to Th1 cells, it is not yet clear whether the α antigen or the α antigen gene is effective for the prevention or treatment of allergic diseases such as atopic dermatitis and asthma for which the mechanism of onset has not been elucidated. In addition, as described above, though the shifting of the Th1 type/Th2 type balance to the Th2 type-dominant state is considered to be important for the establishment of allergic diseases, no reports have been made so far that the mere shifting to the Th1 cell side led to the improvement of skin conditions of atopic dermatitis.